Idiopathic pulmonary fibrosis (IPF) is a highly aggressive lung disease that develops almost exclusively in older individuals and has limited treatment options. An emerging paradigm in the field is that IPF results from chronic repetitive insults that exhaust the lung?s regenerative capacity, causing progressive tissue remodeling that leads to respiratory failure and death in the vast majority of patients. In recent work, we and others have uncovered that lung tissues from IPF patients, old mice and mice with experimentally-induced pulmonary fibrosis undergo a host of metabolic changes, including a marked suppression of lipid synthesis. With this understanding in mind, we recently explored whether restoring lipid synthesis can reduce the severity of pulmonary fibrosis in experimentally-induced mouse models. To test this, we delivered by systemic injection a potent Liver-X Receptor (LXR) agonist (T0901317) to mice. Importantly, we found that T0901317 not only significantly augmented lipid synthesis in the lung but also markedly reduced pathology changes, including decreasing the expression of cellular stress markers and decreasing biochemical and histological evidence of lung fibrosis. Importantly, the rationale for this therapeutic approach is based on the firm understanding that LXR activation induces a host of different lipid synthesis genes and is a well-validated therapeutic target in the drug discovery field. That said, existing LXR agonists are highly stable in the circulation, contributing to numerous long-term side effects such as fatty liver and atherosclerosis. Therefore, in our Phase I SBIR we worked to develop an innovative soft drug approach to targeting LXR activation. This approach utilizes medicinal chemistry to synthesize agonists that work robustly in the lung but become rapidly degraded to inactive compounds upon entry into the circulation. Notably, our work has led to the development of two structurally diverse series of compounds that possess LXR agonist activity and exhibit unstable properties in mouse liver microsomes and plasma. In this Phase I STTR proposal, we seek to further optimize our two series of LXR agonists in order to find preclinical candidates that are optimally suited for intrapulmonary delivery. To achieve this goal, our proposal is divided into three Specific Aims. In Aim 1 we will design and synthesize specific hypothesis-directed additional soft LXR agonists. In Aim 2, we will evaluate each of our compounds to confirm that they undergo rapid metabolic clearance (t1/2 < 10 mins) upon absorption into the circulation using mouse and human plasma and liver microsomes to mimic the in vivo environment. Finally, in Aim 3, 5-7 of our best compounds will be evaluated in vivo for their ability to induce lipid synthesis and ameliorate pulmonary fibrosis in acute and chronic (old mice) bleomycin mouse models, and assess off-target effects of our compounds on other tissues. At the end of this Phase I STTR proposal, we expect to be poised to initiate a full-fledged drug discovery and development program (Phase II STTR) that will enable us develop inhalation formulations that ultimately lead to preclinical drug candidates with suitable efficacy and safety properties to advance directly to IND enabling studies, clinical development and commercialization.